Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice.

Hanna, Zaher; Simard, C; Laperrière, A; Jolicoeur, Paul

doi:10.1128/mcb.14.2.1084

Cited by 57 publications

(60 citation statements)

References 41 publications

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“…We were unable to detect enhancer activity in large restriction fragments that contain the previously identified, proximal enhancer when assayed in D10, AKRlG1, or Jurkat cells (Fig. 1B and (2,22,31).…”

Section: Resultsmentioning

confidence: 96%

Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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The coordinated expression of CD4 and CD8 during T-cell development is tightly coupled with the maturation state of the T cell. Additionally, the mutually exclusive expression of these receptors in mature T cells is representative of the functional T-cell subclasses (CD4+ helper T cells versus CD8+ cytotoxic T cells). We have studied the regulation CD4 gene transcription during T-cell development in an attempt to gain an understanding of the molecular mechanisms involved in T-cell development and differentiation. Here we present the identification of a second transcriptional enhancer in the murine CD4 locus 24 kb upstream of the CD4 promoter. This enhancer is active in mature T cells and is especially active in CD4+ helper T cells. A number of nuclear proteins bind to elements in the minimal CD4 enhancer that includes consensus sites for AP-1, Spl, Gata, and Ets transcription factor families. We find that the Ets consensus site is crucial for enhancer activity and that the recently identified Ets factor, Elf-i, which is expressed at high levels in T cells and involved in the regulation of several other T-cell-specific genes, is a dominant protein in T-cell nuclear extracts that binds to this site.T-cell development involves the differentiation of functionally immature pre-T cells into mature, antigen-reactive effector cells (reviewed in reference 61). This process includes selection events in which the maturing T-cell population is depleted of self-reactive clones and enriched for those that can recognize foreign peptides bound by self-major histocompatibility complex (MHC). The development and selection of T-cell precursors occur in the thymus and are characterized by a coordinated expression of tissue-specific genes. Some of these genes encode cell surface molecules that directly promote T-cell differentiation and selection events. Understanding the molecular mechanisms responsible for the expression of these T-cellspecific genes is a window on the process of T-cell development.The CD4 glycoprotein is one of the surface molecules that is important as a receptor in the development and function of T cells (reviewed in references 39 and 46). In mature antigenspecific T cells, CD4 is expressed only on cells that have a T-cell receptor (TCR) specific for antigen associated with class II MHC molecules, while CD8, a cell surface protein functionally similar to CD4, is expressed only on T cells that recognize antigen bound to MHC class I molecules (56). The mutually exclusive expression of CD4 and CD8 on mature T cells also corresponds to T-cell function; CD4 is expressed primarily on helper T cells, while CD8 is expressed on cytotoxic T cells. CD4 participates in antigen recognition by binding to nonpolymorphic regions of class II MHC molecules, while the T-cell antigen receptor recognizes a specific peptide antigen that is bound by the MHC molecule (7). The CD4-MHC interaction serves to increase the avidity of the T cell to the antigenpresenting cell but also induces an intracellular signaling event through the CD4-...

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Section: Resultsmentioning

confidence: 96%

Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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“…31,32,47,48 No evidence of expression could be documented in smooth, skeletal muscle, endothelial, or in various epithelial cells. To further confirm that Tg expression was restricted in the heart to cells of hematopoietic origin, Tg expression was assessed by in situ hybridization using HIV-1-specific riboprobes, 31 both in CD4C/HIV MutA and CD4C/ HIV MutG Tg hearts.…”

Section: Cell-type Specificity Of Tg Expressionmentioning

confidence: 99%

Cardiac Disease in Transgenic Mice Expressing Human Immunodeficiency Virus-1 Nef in Cells of the Immune System

Kay

Yue

Hanna

et al. 2002

The American Journal of Pathology

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We previously reported that a severe acquired immune deficiency syndrome-like disease develops in transgenic (Tg) mice expressing the human immunodeficiency virus-1 in its natural target cells: immature and mature CD4 ؉ T cells and cells of the macrophage/ dendritic lineage. Here, we show that these mice also develop cardiac disease, characterized most prominently by a focal myocytolysis, occasionally by myocarditis and by deposition of endogenous immunoglobulin on cardiomyocytes. Microfil perfusion demonstrated widespread coronary arteriospasm and echocardiographic analysis revealed depressed cardiac function in Tg mice. A higher (but still modest) level of cardiomyocyte apoptosis was detected in Tg as compared to non-Tg hearts. Tg expression was detected in some of the infiltrating mononuclear cells, but not in cardiomyocytes or in cells of the heart vessels, suggesting a human immunodeficiency virus-1-induced disease process mediated by cells of the immune system. The similarity of the heart disease observed in these Tg mice to that observed in acquired immune deficiency syndrome patients suggests a common pathogenesis.

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“…7 Other constructs were generated from the CD4C DNA by replacing the 2.6-kilobase pair (kbp) SacI fragment with the mouse promoter (CD4E), or the 9-kbp EcoRV-XbaI fragment with the murine silencer (0.5 kbp) (CD4F), or by deleting the 6-kbp EcoRV fragment (CD4H). Tg mice were generated as described elsewhere.…”

Section: Tg Micementioning

confidence: 99%

Distinct regulatory elements are required for faithful expression of human CD4 in T cells, macrophages, and dendritic cells of transgenic mice

Hanna

Rebaï

Poudrier

et al. 2001

Blood

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To identify the regulatory elements controlling expression of the human CD4 (hCD4) gene in different cell types of the immune system, deletion and chimeric (human/murine) reporter genes were constructed and tested in transgenic (Tg) mice. Regulatory elements required for the proper hCD4 expression in the immature double-positive thymic T cells were identified in the enhancer and in the 3 end of intron 1. Expression of hCD4 in macrophages is controlled by at least 2 sets of regulatory elements: one present in front of exon 1 and the second at the 5 end of intron 1. The hCD4 elements required for expression on both myeloid and lymphoid CD8␣ ؉ dendritic cells (DCs) from lymph node and thymus were found IntroductionThe CD4 cell surface receptor is expressed on many mouse or human cell populations, namely, on very early T-cell precursors (CD4 Low CD44 ϩ CD25 Ϫ ), on immature double-positive (DP) CD4 ϩ CD8 ϩ T cells, on mature single-positive (SP) CD4 ϩ CD8 Ϫ T cells, 1,2 and on a subpopulation of CD8␣ Ϫ dendritic cells (DCs). 3,4 In humans, CD4 is also expressed in monocytes, macrophages, microglial cells, and some DCs. 5,6 Several regulatory elements of the murine and human CD4 genes (mCD4, hCD4) have been identified and tested in transgenic (Tg) animal studies (reviewed by Ellmeier et al 1 and Killeen and Littman 2 ). We have exploited the structural homology, but the different patterns of expression, of the mCD4 and hCD4 genes and made chimeric mCD4/hCD4 transgenes, to map more precisely the regulatory regions of the hCD4 gene controlling its expression in macrophages and in DCs. Study design Tg miceConstructs CD4A, CD4B, and CD4C were described previously. 7 Other constructs were generated from the CD4C DNA by replacing the 2.6-kilobase pair (kbp) SacI fragment with the mouse promoter (CD4E), or the 9-kbp EcoRV-XbaI fragment with the murine silencer (0.5 kbp) (CD4F), or by deleting the 6-kbp EcoRV fragment (CD4H). Tg mice were generated as described elsewhere. 7 Flow cytometryCell suspensions were prepared from lymphoid organs and stained with antibodies, as previously described. 7 Peritoneal macrophages were plated overnight. Between 80% and 95% of them stained positive for Mac-1 ( Figure 2B), Mac3, and F4/80 (data not shown). DCs were isolated from lymph node (LN) 8 and thymus. 9 Results and discussionThe Tg mice harboring 6 different DNAs were generated ( Figure 1). Northern blot analysis revealed that expression was highest in the thymus but was also detectable in the spleen and LNs, and was negative in all other organs tested (liver, heart, kidney, lung, intestine, muscle, brain; data not shown). This result is consistent with previous studies indicating that the human and mouse CD4 promoter/enhancer alone or in combination is sufficient to restrict expression to hematopoietic tissues. 7,10-13 As expected, the level of expression varied among different founders carrying the same construct, an effect most likely related to the site of integration of the inoculated DNA.Expression of hCD4 in DP CD4 ؉ CD8 ؉ T ...

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Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice.

Cited by 57 publications

References 41 publications

Elf-1 binds to a critical element in a second CD4 enhancer.

Elf-1 binds to a critical element in a second CD4 enhancer.

Cardiac Disease in Transgenic Mice Expressing Human Immunodeficiency Virus-1 Nef in Cells of the Immune System

Distinct regulatory elements are required for faithful expression of human CD4 in T cells, macrophages, and dendritic cells of transgenic mice

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